EP1858494A2 - New soft gelatin capsules - Google Patents

New soft gelatin capsules

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Publication number
EP1858494A2
EP1858494A2 EP06708736A EP06708736A EP1858494A2 EP 1858494 A2 EP1858494 A2 EP 1858494A2 EP 06708736 A EP06708736 A EP 06708736A EP 06708736 A EP06708736 A EP 06708736A EP 1858494 A2 EP1858494 A2 EP 1858494A2
Authority
EP
European Patent Office
Prior art keywords
capsule
cyclodextrin
shell
weight
hydroxypropyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP06708736A
Other languages
German (de)
French (fr)
Other versions
EP1858494B1 (en
Inventor
Giorgio Zoppetti
Maurizio Marchiorri
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Altergon SA
Original Assignee
Altergon SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Altergon SA filed Critical Altergon SA
Publication of EP1858494A2 publication Critical patent/EP1858494A2/en
Application granted granted Critical
Publication of EP1858494B1 publication Critical patent/EP1858494B1/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • A61K9/4825—Proteins, e.g. gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A61K31/51—Thiamines, e.g. vitamin B1
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135—Compounds containing heavy metals
    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/08—Oxides; Hydroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/10—Carbonates; Bicarbonates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/18—Iodine; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • the present invention relates to a new formulation for soft gelatin capsules which allows an increase in the bioavailability of poorly water soluble or water insoluble active ingredients.
  • soft gelatin capsules The pharmaceutical form known as "soft gelatin capsule” (SEC capsules) is used to administer, mainly orally, non-crystalline and poorly water-soluble active ingredients.
  • SEC capsules preparations of progesterone and vitamin complexes are present on the market in the form of soft gelatin capsules.
  • Soft gelatin capsules are composed of a shell containing plasticized gelatin which encloses a filling material, normally composed of a liquid or semi-liquid lipophilic active ingredient, of a solution of a lipophilic active ingredient or of a pasty product and having characteristics that will not dissolve the shell.
  • a filling material normally composed of a liquid or semi-liquid lipophilic active ingredient, of a solution of a lipophilic active ingredient or of a pasty product and having characteristics that will not dissolve the shell.
  • these formulations have the drawback of often having reduced efficacy due to poor bioavailability of the active ingredients contained therein.
  • Cyclodextrins are cyclic sugars which have the particularity of complexing lipophilic molecules, considerably increasing their water solubility. It is known that progesterone and some vitamins form water-soluble complexes with cyclodextrins, that have thus greater bioavailability compared to the corresponding non complexed compounds.
  • a new soft gelatin capsule consisting of a shell containing a cyclodextrin, preferably selected from ⁇ - cyclodextrin and hydroxypropyl- ⁇ - cyclodextrin (HP ⁇ cyclodextrin), and of a filling material containing a poorly water- soluble or water- insoluble drug and capable of forming a complex with said cyclodextrin.
  • This new formulation shows a stability equivalent to that of conventional soft gelatin capsules and allows to overcome the problem of poor bioavailability of the active ingredients contained therein.
  • Figure 1 represents the dissolution curves of progesterone, obtained with the method coded by the European Pharmacopoeia, from the capsule prepared in Example 2 (curve A) and from a commercial capsule containing an equal amount of progesterone (curves B-D).
  • curve A the curve obtained from the capsule
  • curve B-D the curve obtained from the commercial capsule
  • the curve B was obtained with no cyclodextrin in the dissolution medium
  • the curves C and D were obtained respectively with 50 and 100 mg of hydroxypropyl- ⁇ -cyclodextrin in the dissolution medium.
  • the present invention relates to a soft gelatin capsule consisting of a shell which encloses a filling material (technically called fill) characterized in that the shell contains a cyclodextrin, preferably chosen from ⁇ - cyclodextrin and hydroxypropyl- ⁇ -cyclodextrin, and the filling material contains a poorly water soluble or water-insoluble active ingredient capable of forming a complex with said cyclodextrin.
  • the shell of the capsule of the present invention contains an amount of cyclodextrin ranging from 1% and 30% in weight.
  • cyclodextrin when said cyclodextrin is ⁇ - cyclodextrin, this is contained in the shell of the capsule of the present invention in an amount ranging from 1% to 5%, while when said cyclodextrin is hydroxypropyl- ⁇ -cyclodextrin, this is contained in the shell of the capsule of the present invention in an amount ranging from 5% to 30%.
  • the shell of the capsule of the present invention also contains, just as conventional soft gelatin capsules, gelatin, preferably in an amount ranging from 35% and 50% in weight, a plasticizer, preferably in an amount ranging from 15% to 25% in weight and water, preferably in an amount ranging from 4% to 7% in weight.
  • said plasticizer is a polyhydroxyl alcohol, preferably selected from the group consisting of glycerol, sorbitol, sorbitol/sorbitan mixtures, 1-2 propylene glycol, macrogol 200-600 and mixtures thereof.
  • the filling material of the capsule of the present invention is preferably composed of a solution or suspension of the active ingredient in an oily solvent/ phase.
  • the latter is preferably selected from the group consisting of soy, peanut, sunflower, olive, wheat germ and rape oil, beeswax, hydrogenated coconut oil, refined palm oil, glyceryl monostearate (geleol®) and mixtures thereof.
  • the expression "poorly water soluble or water insoluble active ingredient” according to the present invention indicates active ingredients which have a water solubility of less than 0.1% w/v.
  • active ingredients suitable to be incorporated in the capsule of the present invention are, for example, steroid hormones, liposoluble vitamins or, in general, active ingredients having aromatic rings such as many non- steroid anti-inflammatory drugs (NSAID).
  • NSAID non- steroid anti-inflammatory drugs
  • the capsule of the present invention contains an active ingredient selected from the group consisting of progesterone, liposoluble vitamins, as single vitamins or in mixture with other vitamins and acetylsalicylic acid.
  • the active ingredient is progesterone
  • this is contained in the capsule of the present invention in an amount ranging from 10 to 200 mg and even more preferably of 100 mg.
  • the filling material contains the aforesaid amounts of progesterone and the shell contains from 10 to 22 mg, preferably 20 mg, of hydroxypropyl- ⁇ -cyclodextrin.
  • Liposoluble vitamins are instead contained in the capsules of the present invention preferably in an amount ranging from 0.001 mg to 20 mg, more preferably from 3 to 20 mg and even more preferably of 14 mg.
  • Capsules particularly preferred according to the present invention are those wherein the filling material contains from 3 to 20 mg, preferably 14 mg, of liposoluble vitamins and the shell contains from 1 to 15 mg of ⁇ -cyclodextrin.
  • the aforesaid liposoluble vitamins are preferably selected from the group consisting of vitamin D and of vitamins of the B group.
  • the capsules of the present invention contain acetylsalicylic acid in an amount preferably ranging from 50 to 300 mg per dose, preferably of 88.5 mg.
  • capsules in which the filling material contains from 50 to 300 mg per dose, preferably 88.5 mg, of acetylsalicylic acid and the shell contains from 10 to 150 mg, preferably 55 mg, of hydroxypropyl- ⁇ -cyclodextrin are particularly preferred.
  • the capsules of the present invention are prepared according to the procedures, well known in the art, normally used to prepare soft gelatin capsules, the preferred procedure being the Rotary Die Process.
  • a gastro-resistant and enteric-soluble coating preferably polymeric, is applied to the surface of the shell of the capsule, using techniques well known in the art for the preparation of gastro-resistant capsules.
  • a further object of the present invention is composed of a mix suitable for preparation of the shell of a capsule according to the present invention comprising a cyclodextrin, preferably selected from ⁇ -cyclodextrin and hydroxypropyl- ⁇ -cyclodextrin, gelatin, a plasticizer and water.
  • the plasticizer is a polyhydroxyl alcohol, preferably selected from the group consisting of glycerol, sorbitol, sorbitol/sorbitan mixtures, 1-2 propylene glycol, macrogol 200-600 and mixtures thereof.
  • said mix contains from 0.7% to 20% in weight of cyclodextrin, preferably selected from ⁇ -cyclodextrin and hydroxypropyl- ⁇ -cyclodextrin, from 20% to 50% in weight of gelatin, from 1% to 25% in weight of a plasticizer and from 20 to 50% in weight of water.
  • cyclodextrin preferably selected from ⁇ -cyclodextrin and hydroxypropyl- ⁇ -cyclodextrin
  • cyclodextrin when the aforesaid cyclodextrin is ⁇ -cyclodextrin, this is contained in the aforesaid mix in a quantity ranging from 0.1% to 2.5%, while when the aforesaid cyclodextrin is hydroxypropyl- ⁇ - cyclodextrin, this is contained in the mix of the present invention in a quantity ranging from 1% to 20%.
  • the active ingredients contained in the capsule of the present invention have significantly higher bioavailability than that of the same active ingredients administered with conventional soft gelatin capsules.
  • the capsule of the present invention dissolves in the biological fluids, gradually releasing the cyclodextrin and, once the capsule has been perforated, the content with active ingredient.
  • These two components also favored by the closeness of the molecules, form a complex which increases the water solubility of the active ingredient thereby improving its bioavailability.
  • formulation E is the only one that presents rheological characteristics unsuitable for processing, in particular as it shows excessive adhesiveness that renders it unusable to prepare soft gelatin capsules.
  • all other formulations show suitable rheological characteristics.
  • formulation D appears to be the one with the greatest amount of HP ⁇ -cyclodextrin that is usable.
  • Vit. B6 (Pyridoxine HCl) 0.805 mg Vit. B 12 0.1% 2.400 mg
  • the capsule containing progesterone obtained according to Example 2 was analyzed with the dissolution method according to the European Pharmacopoeia in comparison with a commercial soft gelatin capsule containing 100 mg of progesterone (Utrogestran). Aliquots of solution were taken at regular intervals and analyzed under UV light at 241 nm. The results obtained are set down in Figure 1.
  • dissolution of the progesterone from utrogestran is very modest, due to the almost total insolubility in water of this active ingredient.
  • the capsule of the present invention allows to obtain a dissolution of quantities of progesterone five times greater compared to utrogestran.
  • the effect observed is surprisingly greater than the one obtained from utrogestran by adding hydroxypropyl cyclodextrin to the dissolution medium at the same dosage of the capsule in Example 2 (50 mg) or at double the dosage (100 mg).

Abstract

The present invention relates to soft gelatin capsules characterized in that the shell includes a cyclodextrin and in that the filling material contains a liposoluble drug capable of forming a complex with said cyclodextrin for improving the solubility of the active ingredient upon disintegration of the soft gelatin capsule.

Description

NEW SOFT GELATIN CAPSULES Field of the invention
The present invention relates to a new formulation for soft gelatin capsules which allows an increase in the bioavailability of poorly water soluble or water insoluble active ingredients.
Background art
The pharmaceutical form known as "soft gelatin capsule" (SEC capsules) is used to administer, mainly orally, non-crystalline and poorly water-soluble active ingredients. For example preparations of progesterone and vitamin complexes are present on the market in the form of soft gelatin capsules.
Soft gelatin capsules are composed of a shell containing plasticized gelatin which encloses a filling material, normally composed of a liquid or semi-liquid lipophilic active ingredient, of a solution of a lipophilic active ingredient or of a pasty product and having characteristics that will not dissolve the shell. However, these formulations have the drawback of often having reduced efficacy due to poor bioavailability of the active ingredients contained therein.
Cyclodextrins are cyclic sugars which have the particularity of complexing lipophilic molecules, considerably increasing their water solubility. It is known that progesterone and some vitamins form water-soluble complexes with cyclodextrins, that have thus greater bioavailability compared to the corresponding non complexed compounds.
Nonetheless, these complexes cannot be used in the formulation of soft gelatin capsules, since in this case the solution to be encapsulated would have characteristics that cause solubilization of the gelatin of the shell of the capsules thus rendering the formation, or the stability, of the capsule unachievable. From WO 99/33924 there are known gelatin compositions derived from non-bovine or non-pig, preferably fish origin. To improve the workability, in particular the flowing properties, of the aforementioned "alternative" gelatins, to be employed in the pharmaceutical, veterinary, food or cosmetics field, the incorporation of a setting system comprising hydrocolloids and optionally cations and/or sequestering agents in amounts of less than 5%, preferably 0.01 to 3% is described. Among the sequestering agents employable in the alternative gelatins, also beta-cyclodextrin is mentioned as possible constituent of the setting system. Japanese Patent No. 62-249935 published in 1987 reports of gelatin substrates containing 10 -2% of cyclodextrin, preferably beta-cyclodextrin, displaying improved shelf-life properties, as far as conservation of the so-modified gelatin's disintegration properties is concerned. The preparations employed for the confirmatory tests reported in this publication, do not comprise, however, the inclusion of active principles.
Therefore, the problem remains of developing formulations of soft gelatin capsules which allow the bioavailability of the drugs contained therein to be increased.
Summary of the invention
It has now surprisingly been found new formulation in capsule which allows the bioavailability of the poorly soluble active ingredients to be increased. In particular, the present inventors have developed a new soft gelatin capsule consisting of a shell containing a cyclodextrin, preferably selected from β- cyclodextrin and hydroxypropyl- β- cyclodextrin (HPβ cyclodextrin), and of a filling material containing a poorly water- soluble or water- insoluble drug and capable of forming a complex with said cyclodextrin. This new formulation shows a stability equivalent to that of conventional soft gelatin capsules and allows to overcome the problem of poor bioavailability of the active ingredients contained therein. Description of the figures Figure 1 represents the dissolution curves of progesterone, obtained with the method coded by the European Pharmacopoeia, from the capsule prepared in Example 2 (curve A) and from a commercial capsule containing an equal amount of progesterone (curves B-D). With regard to the curves obtained from the commercial capsule, the curve B was obtained with no cyclodextrin in the dissolution medium, while the curves C and D were obtained respectively with 50 and 100 mg of hydroxypropyl- β -cyclodextrin in the dissolution medium.
Detailed description of the invention
The present invention relates to a soft gelatin capsule consisting of a shell which encloses a filling material (technically called fill) characterized in that the shell contains a cyclodextrin, preferably chosen from β- cyclodextrin and hydroxypropyl- β -cyclodextrin, and the filling material contains a poorly water soluble or water-insoluble active ingredient capable of forming a complex with said cyclodextrin. Preferably, the shell of the capsule of the present invention contains an amount of cyclodextrin ranging from 1% and 30% in weight.
In particular, according to a preferred embodiment of the present invention, when said cyclodextrin is β- cyclodextrin, this is contained in the shell of the capsule of the present invention in an amount ranging from 1% to 5%, while when said cyclodextrin is hydroxypropyl- β -cyclodextrin, this is contained in the shell of the capsule of the present invention in an amount ranging from 5% to 30%.
The shell of the capsule of the present invention also contains, just as conventional soft gelatin capsules, gelatin, preferably in an amount ranging from 35% and 50% in weight, a plasticizer, preferably in an amount ranging from 15% to 25% in weight and water, preferably in an amount ranging from 4% to 7% in weight.
Preferably, said plasticizer is a polyhydroxyl alcohol, preferably selected from the group consisting of glycerol, sorbitol, sorbitol/sorbitan mixtures, 1-2 propylene glycol, macrogol 200-600 and mixtures thereof. The filling material of the capsule of the present invention is preferably composed of a solution or suspension of the active ingredient in an oily solvent/ phase. The latter is preferably selected from the group consisting of soy, peanut, sunflower, olive, wheat germ and rape oil, beeswax, hydrogenated coconut oil, refined palm oil, glyceryl monostearate (geleol®) and mixtures thereof. The expression "poorly water soluble or water insoluble active ingredient" according to the present invention indicates active ingredients which have a water solubility of less than 0.1% w/v.
In particular, active ingredients suitable to be incorporated in the capsule of the present invention are, for example, steroid hormones, liposoluble vitamins or, in general, active ingredients having aromatic rings such as many non- steroid anti-inflammatory drugs (NSAID).
According to a particularly preferred application, the capsule of the present invention contains an active ingredient selected from the group consisting of progesterone, liposoluble vitamins, as single vitamins or in mixture with other vitamins and acetylsalicylic acid.
Preferably, when the active ingredient is progesterone, this is contained in the capsule of the present invention in an amount ranging from 10 to 200 mg and even more preferably of 100 mg. Particularly preferred is a capsule wherein the filling material contains the aforesaid amounts of progesterone and the shell contains from 10 to 22 mg, preferably 20 mg, of hydroxypropyl- β-cyclodextrin.
Liposoluble vitamins, as single vitamins or in mixture with other vitamins, are instead contained in the capsules of the present invention preferably in an amount ranging from 0.001 mg to 20 mg, more preferably from 3 to 20 mg and even more preferably of 14 mg. Capsules particularly preferred according to the present invention are those wherein the filling material contains from 3 to 20 mg, preferably 14 mg, of liposoluble vitamins and the shell contains from 1 to 15 mg of β-cyclodextrin. The aforesaid liposoluble vitamins are preferably selected from the group consisting of vitamin D and of vitamins of the B group. Particularly preferred is a mixture of the aforesaid vitamins containing from 5 to 15 μg of vitamin D, from 0.5 to 2 mg of vitamin Bl (Thiamine), from 0.5 to 3 mg of vitamin B2 (Riboflavin), from 0.5 to 2 mg of vitamin B6, from 5 to 20 μg of vitamin B 12, from 400 to 800 μg of vitamin A, from 50 to 150 μg of vitamin H (Biotin), from 1 to 10 mg of vitamin E.
According to a further embodiment, the capsules of the present invention contain acetylsalicylic acid in an amount preferably ranging from 50 to 300 mg per dose, preferably of 88.5 mg. Among these, capsules in which the filling material contains from 50 to 300 mg per dose, preferably 88.5 mg, of acetylsalicylic acid and the shell contains from 10 to 150 mg, preferably 55 mg, of hydroxypropyl- β-cyclodextrin are particularly preferred.
The capsules of the present invention are prepared according to the procedures, well known in the art, normally used to prepare soft gelatin capsules, the preferred procedure being the Rotary Die Process. According to a further embodiment of the capsule of the present invention, if it is desirable for the capsule to pass through the stomach unaltered and only release its content at the level of the intestine, for example in the case of drugs which deteriorate in an acid environment, a gastro-resistant and enteric-soluble coating, preferably polymeric, is applied to the surface of the shell of the capsule, using techniques well known in the art for the preparation of gastro-resistant capsules.
A further object of the present invention is composed of a mix suitable for preparation of the shell of a capsule according to the present invention comprising a cyclodextrin, preferably selected from β-cyclodextrin and hydroxypropyl- β-cyclodextrin, gelatin, a plasticizer and water. Preferably, the plasticizer is a polyhydroxyl alcohol, preferably selected from the group consisting of glycerol, sorbitol, sorbitol/sorbitan mixtures, 1-2 propylene glycol, macrogol 200-600 and mixtures thereof. Preferably, said mix contains from 0.7% to 20% in weight of cyclodextrin, preferably selected from β-cyclodextrin and hydroxypropyl- β-cyclodextrin, from 20% to 50% in weight of gelatin, from 1% to 25% in weight of a plasticizer and from 20 to 50% in weight of water. According to a preferred embodiment of the present invention, when the aforesaid cyclodextrin is β-cyclodextrin, this is contained in the aforesaid mix in a quantity ranging from 0.1% to 2.5%, while when the aforesaid cyclodextrin is hydroxypropyl- β- cyclodextrin, this is contained in the mix of the present invention in a quantity ranging from 1% to 20%.
The active ingredients contained in the capsule of the present invention have significantly higher bioavailability than that of the same active ingredients administered with conventional soft gelatin capsules.
In fact, upon reaching the stomach, or, in the case of gastro-resistant capsules, the intestine, the capsule of the present invention dissolves in the biological fluids, gradually releasing the cyclodextrin and, once the capsule has been perforated, the content with active ingredient. These two components, also favored by the closeness of the molecules, form a complex which increases the water solubility of the active ingredient thereby improving its bioavailability. EXAMPLES EXAMPLE 1
The solubility of β-, γ and hydroxypropyl- β- (HPβ) cyclodextrin in the solution containing gelatin was verified. This study was conducted by dissolving quantities of 2.5% or of 5%
(W/V) of β-, γ or hydroxypropyl- β- (HPβ) cyclodextrin in an aqueous solution containing
36% (WAV) of gelatin and 15% (WAV) of anhydrous glycerin.
The results obtained show that only γ-cyclodextrin and hydroxypropyl- β-cyclodextrin are soluble at 5% in the aforesaid solution, while β-cyclodextrin is soluble in the aforesaid solution at a concentration of 2.5%, while at a concentration of 5% it produces an opalescent mixture. Therefore, in the evaluation of the tests performed it was decided to continue by using beta cyclodextrin for the capsules with a low cyclodextrin content and using HPBCD cyclodextrin for those with a high cyclodextrin content.
In the latter case, the maximum solubility obtainable was analyzed by preparing solutions at different concentrations.
The following formulations were taken into consideration:
At all the concentrations tested solubilization of the HPβ-cyclodextrin in the gelatin formulation was observed.
The results obtained show that among the formulations tested, E is the only one that presents rheological characteristics unsuitable for processing, in particular as it shows excessive adhesiveness that renders it unusable to prepare soft gelatin capsules. On the contrary, all other formulations show suitable rheological characteristics. In particular, formulation D appears to be the one with the greatest amount of HPβ-cyclodextrin that is usable.
EXAMPLE 2
Preparation of soft gelatin capsules with high cyclodextrin content containing progesterone. a) preparation of the mix for the shell
25.9 liters of purified water are added to 13.65 kg of HPβ-cyclodextrin (Kleptose HP-β by Roquette Freres -Fr) and kept under stirring for 15-60 minutes at 3O0C. When a limpid solution is obtained 9.1 kg of anhydrous glycerin are added, continuing the stirring, and the temperature is brought to 7O0C, then 21 kg of gelatin are added and the mixture obtained is kept under stirring for 15-60 minutes. The mass is then deaerated by applying a progressive vacuum until reaching a value ranging from -0.8 to -0.9 bar. b) preparation of the progesterone filling material The following formulation was prepared: Progesterone 100 mg
Peanut oil and soy lecithin qs to 250 mg c) preparation of the capsules Oval, size 5 soft gelatin capsules were prepared according to the process known as Rotary Die Process. Capsules with the following characteristics were obtained:
• mean weight per capsule: 418 mg
• residual humidity: 5.8 • progesterone content: 96.3 mg/capsule
• disintegration time, measured according to the method coded by the European Pharmacopoeia: 15 minutes
EXAMPLE 3
Preparation of soft gelatin capsules with a high cyclodextrin content containing acetylsalicylic acid a) Preparation of the mix for the shell
The mix for the shell was prepared as described in Example 2. b) Preparation of the filling material containing acetylsalicylic acid The following formulation was prepared: acetylsalicylic acid 100 mg excipients qs to 402 mg
(Epax 5500 TG, soy lecithin, beeswax, hydrogenated coconut oil, refined palm oil, delta tocopherol). c) Oval, size 7.5 soft gelatin capsules were prepared according to the process known as Rotary Die Process.
Capsules having the following characteristics were obtained:
• mean weight per capsule: 644 mg
• residual humidity, according to the Karl Fisher method: 5.3%
• acetylsalicylic acid content: 88.56 mg/capsule • dissolution time, measured according to the European Pharmacopoeia method: 15 minutes EXAMPLE 4
Preparation of soft gelatin capsules with a low cyclodextrin content containing a multivitamin complex a) Preparation of the mix for the shell 23 liters of purified water (including an additional dose of 5 1) are added to 1.00 kg of beta cyclodextrin (Cavasol W7 by Roquette Freres -France) and kept under stirring until completely dissolved at 7O0C. When a limpid solution is obtained, 1.0 kg of anhydrous glycerin and, subsequently, 21.7 kg of gelatin are added. The mass is then deaerated by applying a progressive vacuum to eliminate excess water. b) Preparation of the filling material containing the multivitamin compound The following formulation was prepared:
Heavy calcium carbonate 125 mg
Heavy magnesium oxide 149 mg
Zinc sulphate monohydrate 20.550 mg Vit E Nat. 7.452 mg
Vit D3 in oil (1 MIO IU/GR) 0.240 mg
Vit. Bl (Thiamine mononitrate) 0.600 mg
Vit. B2 (Riboflavin) 0.770 mg
Vit. B6 (Pyridoxine HCl) 0.805 mg Vit. B 12 0.1% 2.400 mg
Potassium iodide 0.100 mg
Selenium yeast (2000 mcg/g) 25.00 mg
GMO-free soy oil, Geleol, GMO-free soy lecithin, qs to 655.561 mg c) Preparation of the soft capsules The aforesaid preparations were subsequently utilized to produce oval size 10 soft capsules, according to the process known as Rotary Die Process.
Soft capsules with the following characteristics were obtained:
• mean weight per capsule: 88 mg
• residual humidity: 5.4% • multivitamin complex content: 680 mg/capsule EXAMPLE 5
The capsule containing progesterone obtained according to Example 2 was analyzed with the dissolution method according to the European Pharmacopoeia in comparison with a commercial soft gelatin capsule containing 100 mg of progesterone (Utrogestran). Aliquots of solution were taken at regular intervals and analyzed under UV light at 241 nm. The results obtained are set down in Figure 1.
As can be seen from the figure, dissolution of the progesterone from utrogestran is very modest, due to the almost total insolubility in water of this active ingredient. On the contrary, the capsule of the present invention allows to obtain a dissolution of quantities of progesterone five times greater compared to utrogestran.
The effect observed is surprisingly greater than the one obtained from utrogestran by adding hydroxypropyl cyclodextrin to the dissolution medium at the same dosage of the capsule in Example 2 (50 mg) or at double the dosage (100 mg).

Claims

1. Use of cyclodextrin in a soft gelatin capsule consisting of a shell enclosing a filling material characterized in that the shell contains a cyclodextrin and the filling material contains a poorly water-soluble or water-insoluble active ingredient capable of forming a complex with said cyclodextrin for improving the solubility of the active ingredient upon disintegration of the soft gelatin capsule.
2. Use as claimed in claim 1, wherein the shell of the capsule contains an amount of cyclodextrin ranging from 1% to 30% in weight.
3. Use as claimed in claim 1 or 2, wherein the aforesaid cyclodextrin is selected from β- cyclodextrin and hydroxypropyl- β -cyclodextrin.
4. Use as claimed in claim 3, the shell of the capsule containing a quantity of β- cyclodextrin ranging from 1% to 5%.
5. Use as claimed in claim 3, the shell of the capsule containing a quantity of hydroxypropyl- β -cyclodextrin ranging from 5% to 30%, preferably more than 10% to 30%.
6. Use as claimed in claims 1 to 5, wherein the shell of the capsule contains gelatin in an amount ranging from 35% to 50% in weight, plasticizer in an amount ranging from 15% to 25% in weight and water in an amount ranging from 4% to 7% in weight.
7. Use as claimed in claims 1 to 6, wherein the plasticizer contained in the shell of the capsule is a polyhydroxyl alcohol.
8. Use as claimed in claim 7, wherein the plasticizer is selected from the group composed of glycerol, sorbitol, sorbitol/sorbitan mixtures, 1-2 propylene glycol, macrogol 200- 600 and mixtures thereof
9. Use as claimed in claims 1 to 8, wherein the filling material of the capsule consists of a solution or suspension of the active ingredient in an oily solvent/phase.
10. Use as claimed in claim 9, wherein said oily solvent/phase is selected from the group consisting of soy, peanut, sunflower, olive, wheat germ and rape oil, beeswax, hydrogenated coconut oil, refined palm oil, glyceryl monostearate (geleol®) and mixtures thereof.
11. Use as claimed in claims 1 to 10, wherein said active ingredient contained in the filling material of the capsule is selected from the group consisting of steroid hormones, liposoluble vitamins and active ingredients having aromatic rings.
12. Use as claimed in claim 11, wherein said active ingredients having aromatic rings are non- steroid anti-inflammatory drugs.
13. Use as claimed in claim 11, wherein said active ingredient is selected from the group consisting of progesterone, liposoluble vitamins, as single vitamins or in mixture with other vitamins, and acetylsalicylic acid.
14. Use as claimed in claim 13, the filling material of the capsule containing progesterone in an amount ranging from 10 to 200 mg.
15. Use as claimed in claim 14, the filling material of the capsule containing 100 mg of progesterone.
16. Use as claimed in claim 14 or 15, wherein the shell of the capsule contains from 10 to 22 mg of hydroxypropyl- β-cyclodextrin.
17. Use as claimed in claim 16, wherein the shell of the capsule contains 20 mg of hydroxypropyl- β-cyclodextrin.
18. Use as claimed in claim 13, the filling material of the capsule containing liposoluble vitamins in an amount ranging from 0.001 mg to 20 mg.
19. Use as claimed in claim 18, wherein the filling material of the capsule contains from 3 to 20 mg of liposoluble vitamins.
20. Use as claimed in claim 19, the filling material of the capsule containing 14 mg of liposoluble vitamins.
21. Use as claimed in claim 19 or 20, wherein the shell contains from 1 to 15 mg of β- cyclodextrin.
22. Use as claimed in claims 18 to 21, the filling material of the capsule containing from 5 to 15 μg of vitamin D, from 0.5 to 2 mg of vitamin Bl (Thiamine), from 0.5 to 3 mg of vitamin B2 (Riboflavin), from 0.5 to 2 mg of vitamin B6, from 5 to 20 μg of vitamin B 12, from 400 to 800 μg of vitamin A, from 50 to 150 μg of vitamin H (Biotin), from 1 to 10 mg of vitamin E.
23. Use as claimed in claim 13, the filling material of the capsule containing acetylsalicylic acid in a quantity ranging from 50 to 300 mg.
24. Use as claimed in claim 23, the filling material of the capsule containing 88.5 mg of acetylsalicylic acid.
25. Use as claimed in claim 23 or 24, wherein the shell of the capsule contains from 10 to 150 mg of hydroxypropyl- β-cyclodextrin.
26. Use as claimed in claim 25, wherein the shell of the capsule contains 55 mg of hydroxypropyl- β-cyclodextrin.
27. Use as claimed in claims 1 to 26, wherein the shell of the capsule is coated with a gastro-resistant and enteric- soluble coating.
28. Use of cyclodestrin for the preparation of the shell of capsules as referred to in claims 1 to 26.
29. Use as claimed in claim 28, the shell of the capsule containing from 0.7% to 20% in weight of cyclodextrin, from 20% to 50% in weight of gelatin, from 1% to 25% in weight of a plasticizer and from 20 to 50% in weight of water.
30. Use as claimed in claim 29, wherein said cyclodextrin is β-cyclodextrin and is contained in the mix in a quantity ranging from 0.1% to 2.5% in weight.
31. Use as claimed in claim 29, wherein said cyclodextrin is hydroxypropyl- β-cyclodextrin and is contained in the mix in a quantity ranging from 1% to 20% in weight.
32. Soft gelatin capsule consisting of a shell enclosing a filling material characterized in that the shell contains a hydroxypropyl beta- cyclodextrin and the filling material contains a poorly water-soluble or water-insoluble active ingredient capable of forming a complex with said hydroxypropyl beta- cyclodextrin.
33. Capsule as claimed in claim 32, wherein the shell contains an amount of hydroxypropyl beta- cyclodextrin ranging from 1% to 30% in weight.
34. Capsule as claimed in claim 33, containing a quantity of hydroxypropyl- β-cyclodextrin ranging from 5% to 30%.
35. Capsule as claimed in claim 34, containing a quantity of hydroxypropyl beta- cyclodextrin ranging from more than 10% to 30%.
36. Capsule as claimed in claims 32 to 35, wherein the shell contains gelatin in an amount ranging from 35% to 50% in weight, plasticizer in an amount ranging from 15% to
25% in weight and water in an amount ranging from 4% to 7% in weight.
37. Capsule as claimed in claims 32 to 36, wherein the plasticizer is a polyhydroxyl alcohol.
38. Capsule as claimed in claim 37, wherein the plasticizer is selected from the group composed of glycerol, sorbitol, sorbitol/sorbitan mixtures, 1-2 propylene glycol, macrogol 200-600 and mixtures thereof
39. Capsule as claimed in claims 32 to 38, wherein the filling material consists of a solution or suspension of the active ingredient in an oily solvent/phase.
40. Capsule as claimed in claim 39, wherein said oily solvent/phase is selected from the group consisting of soy, peanut, sunflower, olive, wheat germ and rape oil, beeswax, hydrogenated coconut oil, refined palm oil, glyceryl monostearate (geleol®) and mixtures thereof.
41. Capsule as claimed in claims 32 to 40, wherein said active ingredient is selected from the group consisting of steroid hormones, liposoluble vitamins and active ingredients having aromatic rings.
42. Capsule as claimed in claim 41, wherein said active ingredients having aromatic rings are non- steroid anti-inflammatory drugs.
43. Capsule as claimed in claim 42, wherein said active ingredient is selected from the group consisting of progesterone, liposoluble vitamins, as single vitamins or in mixture with other vitamins, and acetylsalicylic acid.
44. Capsule as claimed in claim 43, containing progesterone in an amount ranging from 10 to 200 mg.
45. Capsule as claimed in claim 44, containing 100 mg of progesterone.
46. Capsule as claimed in claim 44 or 45, wherein the shell contains from 10 to 22 mg of hydroxypropyl- β-cyclodextrin.
47. Capsule as claimed in claim 46, wherein the shell contains 20 mg of hydroxypropyl- β- cyclodextrin.
48. Capsule as claimed in claim 43, containing liposoluble vitamins in an amount ranging from 0.001 mg to 20 mg.
49. Capsule as claimed in claim 48, wherein the filling material contains from 3 to 20 mg of liposoluble vitamins.
50. Capsule as claimed in claim 49, containing 14 mg of liposoluble vitamins.
51. Capsule as claimed in claims 48 to 50, containing from 5 to 15 μg of vitamin D, from
0.5 to 2 mg of vitamin Bl (Thiamine), from 0.5 to 3 mg of vitamin B2 (Riboflavin), from 0.5 to 2 mg of vitamin B6, from 5 to 20 μg of vitamin B 12, from 400 to 800 μg of vitamin A, from 50 to 150 μg of vitamin H (Biotin), from 1 to 10 mg of vitamin E.
52. Capsule as claimed in claim 43, containing acetylsalicylic acid in a quantity ranging from 50 to 300 mg.
53. Capsule as claimed in claim 52, containing 88.5 mg of acetylsalicylic acid.
54. Capsule as claimed in claim 52 or 53, wherein the shell contains from 10 to 150 mg of hydroxypropyl- β-cyclodextrin.
55. Capsule as claimed in claim 54, wherein the shell contains 55 mg of hydroxypropyl- β- cyclodextrin.
56. Capsule as claimed in claims 32 to 55, wherein the shell is coated with a gastro- resistant and enteric- soluble coating.
57. Mix for preparation of the shell of capsules as claimed in claims 32 to 56.
58. Mix as claimed in claim 57, containing from 0.7% to 20% in weight of hydroxypropyl beta-cyclodextrin, from 20% to 50% in weight of gelatin, from 1% to 25% in weight of a plasticizer and from 20 to 50% in weight of water.
59. Mix as claimed in claim 58, wherein said hydroxypropyl- β-cyclodextrin is contained in the mix in a quantity ranging from 1% to 20% in weight.
EP06708736A 2005-03-11 2006-03-13 New soft gelatin capsules Active EP1858494B1 (en)

Applications Claiming Priority (2)

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IT000387A ITMI20050387A1 (en) 2005-03-11 2005-03-11 NEW SOFT JELLY CAPSULES
PCT/EP2006/060649 WO2006095026A2 (en) 2005-03-11 2006-03-13 New soft gelatin capsules

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ITMI20061672A1 (en) * 2006-09-01 2008-03-02 Altergon Sa FORMULATIONS OF ACETYLSALICYLIC ACID OR ITS DERIVATIVES IN SOFT CAPSULES, EXHIBITING HIGH STABILITY
US8287904B2 (en) * 2010-08-19 2012-10-16 Lionel Borkan Stable soft capsule dosage form for acetylsalicylic acid
CN104311887A (en) * 2014-09-19 2015-01-28 江苏崇尚生物科技有限公司 Raw material composition for preparing starch matrix hollow capsule and starch matrix hollow capsule
KR101550322B1 (en) 2015-02-27 2015-09-04 김재훈 composition for soft capsule shell
WO2017095736A1 (en) * 2015-12-01 2017-06-08 R.P. Scherer Technologies, Llc Aspirin soft gelatin capsule as a single active or in combination with other actives
CN106074434B (en) * 2016-07-06 2019-01-18 中国科学院化学研究所 A kind of feedstock composition and Capsules preparing starch matrix Capsules
IT201700015145A1 (en) * 2017-02-10 2018-08-10 Altergon Sa High stability soft gelatin capsules
IT201900013557A1 (en) * 2019-07-31 2021-01-31 Univ Degli Studi Di Sassari ANIMAL JELLIES MODIFIED WITH CYCLODEXTRINS, PROCEDURE FOR THEIR PREPARATION, FILMS OBTAINED FROM THE SAME AND THEIR USE IN THE PACKAGING FIELD

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JPS62249935A (en) 1986-04-18 1987-10-30 Toyo Kapuseru Kk Cyclodextrin-containing gelatin substrate for drug preparation
ID25786A (en) 1997-12-26 2000-11-02 Warner Lambert Co GELATIN COMPOSITION
US20030104048A1 (en) * 1999-02-26 2003-06-05 Lipocine, Inc. Pharmaceutical dosage forms for highly hydrophilic materials
US6262086B1 (en) * 1999-08-26 2001-07-17 Robert R. Whittle Pharmaceutical unit dosage form

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CA2600969A1 (en) 2006-09-14
DE602006003073D1 (en) 2008-11-20
KR20070112252A (en) 2007-11-22
CN101141952B (en) 2011-12-28
KR101342486B1 (en) 2013-12-19
EP1858494B1 (en) 2008-10-08
WO2006095026A3 (en) 2007-01-11
DK1858494T3 (en) 2009-02-02
PT1858494E (en) 2009-01-14
ES2314884T3 (en) 2009-03-16
US20080206323A1 (en) 2008-08-28
US9168229B2 (en) 2015-10-27
US8728519B2 (en) 2014-05-20
WO2006095026A8 (en) 2007-12-13
CN101141952A (en) 2008-03-12
WO2006095026A2 (en) 2006-09-14

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